This is a resubmission of a project whose overall aim is to assess the effects of genetic vulnerability to alcoholism on the developing adolescent brain, using cognitive assessments and functional and structural brain imaging. The University of Iowa is one of several sites that have participated in the Collaborative Studies on Genetics of Alcoholism (COGA) project since 1989. COGA is funded by NIAAA (U10AA008401) with the goal of identifying specific genes underlying vulnerability to alcoholism and related disorders. COGA recently began a prospective study, assessing adolescents every two years, beginning at age 12. The project proposed here would assess adolescent COGA volunteers from high genetic risk (HGR) families with state-of-the-art measures of brain structure, using structural magnetic resonance imaging (MRI) measures, and brain function, assessed both by functional MRI (fMRI) and cognitive assessment. The fMRI tasks will focus upon the forebrain reward system, and frontal lobe inhibitory function. Over a five-year period we propose to recruit a group of 96, 13-18 year old HGR COGA subjects, who have minimal use of alcohol and other recreational drugs, and 96 age and gender matched low genetic risk (LGR) controls. Exclusion criteria for both groups will include any history of a psychiatric or neurologic disorder other than conduct disorder. Because conduct disorder (CD) is the most frequent co-morbid psychiatric disorder in adolescents and adults with alcohol use disorders (AUDs) we will recruit HGR subjects with a range of CD symptoms. Regression analyses will then be used to assess the unique variance in the dependent variables associated with CD versus genetic risk for alcohol disorders. We will assess whether adolescents at genetic risk for developing alcohol problems differ from normal adolescent volunteers in brain morphology, activation patterns on fMRI tasks, and/or performance on a range of cognitive tasks that have been shown to be associated with AUD or CD. Although adolescents meeting the rigorous inclusion criteria will be recruited at several of the COGA sites, the neuroimaging and cognitive assessments will take place exclusively in Iowa. While it is feasible to collect imaging data at each site, our experience with the functional Brain Informatics Research Network (fBIRN) project (Dr. O'Leary is the Iowa site PI) indicates that acquiring compatible imaging data at multiple sites requires considerable expense and effort, raises the possibility of non-uniform assessment, and is typically worthwhile only when very large numbers of subjects are required. Our strategy of using a smaller number of adolescent subjects with pedigrees densely affected with alcoholism, selected according to rigorous criteria, makes good use of the extensive COGA data base that has already been collected. The brain imaging and cognitive assessments of adolescents that we propose will provide important information concerning brain structure and function that will profit synergistically from the existing COGA data base, and add information that has both basic science and clinical significance. PUBLIC HEALTH RELEVANCE: Alcoholism and related problems have been shown to have a genetic component. This project will determine whether adolescents who are at genetic risk of developing alcohol-related problems have differences from other adolescents in brain structure and/or function before they start abusing alcohol or other drugs.